The overall goal of this Program remains to understand how basic cellular processes are altered to promote tumor initiation and progression and how such alterations might make tumor cells vulnerable to specific, targeted interventions. Initiated by James Watson in 1968, the program focused on the action of DNA tumor viruses and in many ways powered the molecular biology revolution. Throughout its history, it revealed the underpinnings of basic biological processes central to cancer development and revealed key oncogenic mechanisms affecting their action. Taking advantage of new biological concepts and technologies emerging from its investigators, the Program has continued to innovate and evolve, with an ever greater focus on mechanisms of immediate biological and therapeutic relevance to the human disease. Over the last funding period, the Program produced fundamentally new insights into DNA replication its coordination in normal and cancer cells, and established that aberrant alternative RNA splicing is an important oncogenic mechanism. The Program has been at the forefront of non-coding RNA biology, providing some of the first evidence that microRNAs can act as oncogenes and tumor suppressors, and influence other key cancer phenotypes. Lastly, the Program has developed and implemented innovative mouse models and used them to identify new oncogenes and tumor suppressors of broad relevance to human cancer. Armed with new technologies developed by Program investigators over the last several years, we will implement a multi pronged approach towards identifying novel oncogenic mechanisms, with an eye towards revealing the vulnerabilities they create. Some elements of the Program are driven from the standpoint of particular cellular processes, such as chromosome replication and segregation or pre-mRNA splicing (Projects 1 and 2), and others implement unbiased approaches informed by changes in the cancer genome or alterations in regulatory networks to focus their studies (Projects 3-5). All Projects converge on potential anticancer targets, whose efficacy can be predicted based upon the nature or state of the cancer cell or its microenvironment. All of the Projects benefit from demonstrable interactions among themselves, taking advantage of complementary approaches and expertise. Moreover, each Project benefits from the four innovative Cores, each of wtiich is lead by outstanding and experienced researchers. Finaily, the Program benefits from, and contributes to, the collaborative environment fostered by the Coid Spring Harbor Laboratory Cancer Center and is at the heart of its activities.